All right, I think we'll get started here with our next fireside discussion. So, again, my name is Derek Archila. I'm one of the Wells Fargo Biotech Analysts. And our next fireside presenter here is C4 Therapeutics. From the company, we have the CEO, Andy Hirsch, and then also we have the Chief Medical Officer, Len Reyno. So, gentlemen, thanks so much for joining us. Great. Thanks for having us. So maybe just to start off high level, you know, just give us the sense of, you know, what you guys are working on, and then we can kind of dig into the specific programs. Yeah. So it's been an exciting year for the company. You know, we've progressed the two clinical programs that we are operationalizing. That's the cemsidomide program, and CFT-1946, which is our BRAF V600X degrader. Both of them are currently in phase 1 dose escalation studies, and we've made a lot of progress in terms of moving through escalation cohorts and expansion cohorts, which you've shared throughout the year. And so I'm really pleased with the execution of the team, and that's really going to pay off as we have two important data readouts, you know, coming up at... In In about a week at ESMO, we have the first data that we'll share on 1946, which is the BRAF program, which we're really looking forward to sharing that as a program. Not many people have talked about, but something we're very excited about. Hopefully, that data, when we share that, we'll. Everyone will see why, we like the program. And then cemsidomide, we shared data in December of last year, with a complete monotherapy cohort for that program, and that's our IKZF1/3 degrader for multiple myeloma, non-Hodgkin lymphoma. In the fourth quarter, we'll share the more robust data set of the plus dexamethasone cohort, as well as the NHL data. So we're really kind of busy back end of the year, but really excited about it. Yeah, very exciting. So well, let's talk about the BRAF degrader. So, maybe just talk about the target and some of the challenges and why a degrader approach there, you know, makes sense. Yeah, and that's why we really like the program, because, you know, one of the limitations of the BRAF inhibitors, which actually do a nice job and are pretty entrenched in treatment for, you know, melanoma, for CRC and for lung cancer in patients with a BRAF mutation, but they all have the same liability in that they have resistance mechanisms that lead to poor durability, and the primary method of that resistance is the monomer can be inhibited, and that stops the signaling through the MAPK pathway, but what can happen is that stops the monomer signaling, but what happens is that inhibited monomer can dimerize with other family members and then can lead to the additional signaling. That leads to a host of different types of resistance mechanisms. We think a degrader is actually the best solution for that, where we just remove the protein completely. Not only does it stop the monomer signaling. But the protein's no longer there, and so it can't dimerize and lead to that aberrant signaling and the resistance mechanisms that occur. And so we think, you know, that that's a much better way to do it. And then the other benefit of degrader, this is a class effect, is degraders can be highly selective because we sort of are engineering it so that the ligase can only degrade the mutant protein. And so, as we've shown in our preclinical data, we spare wild type. So the other challenge with inhibitors is you have a lot of skin tox, and so that's really the result of inhibiting wild type BRAF. And so we spare wild type BRAF from our degrader, and that's been shown in our global proteome experiments. And so, you know, we should have a better safety profile as well. Got it. So I guess maybe just tee up. So this is dose escalation. You know, what's kind of the expectations around, you know, how many patients might be presented? Like, how should we interpret this data? Yeah. So what we've guided to is at least four dose levels and at least 30 patients. And that's across, you know, the escalation that we've done. So, we've gone from. We start at 20- Twenty ... to 80 to 160, 320, and 640 is the highest dose so far. Actually, a bit of an update on the Q2 announcement, we said we'd fully enrolled the 640 escalation cohort, but had not yet declared it safe. We've now declared it safe and are expanding into our PK/PD expansion cohorts, which we can talk about. Len, if you want to share about the design. Yeah, I was going to. This might be a good jumping-off point to sort of take that and drill down a little bit on the trial design. Because I think one of the things that we're most proud of is that it's a really thoughtful trial design, really designed to maximize the value of a small data set. You all want to know, so do clinicians, as soon as possible, that the drug has promise. And so we- Do we have a drug? Do we have a drug? And so we designed the program to answer that question as quickly as possible. And so let's think about from first principles how to do that. First is, who do you treat? Okay, so one of the things that we set out to do was to treat patients who have the clinical problem. And the clinical problem is patients are showing up to clinic, having had been previously treated with inhibitor regimens, who have progressed but still have a BRAF mutation that's driving their cancers. So that's the clinical problem. Who are those patients? So the bulk of those patients come from four groups. One, the biggest group, is melanoma. The second biggest group is colorectal cancer, the third biggest group is lung cancer, and the fourth group is a smattering of other malignancies, not in those three histologies, which have a driver mutation, which include things like pancreatic cancer or cholangiocarcinoma. So then we set out, we recruited sites that would give us patients with a mix of that. So those sites are actually recruiting, have been recruiting patients on both sides of the Atlantic, with sites in the U.S., France and Spain. And I should parenthetically add, incredible investigator enthusiasm for this because it resonates with people why a degrader might be interesting. So in terms of the trial itself, on the one hand, it's a standard monotherapy dose escalation. It is driven by a Bayesian logistic regression model. Why is that important? It's important because it's not a three plus three design and the cohort size is not pre-specified. And sometimes when people look in at cohorts, they think, "Well, that cohort had six, they must have had toxicity." That's the wrong inference to take using BLRM, but that's the first step, so we go through the five dose levels that Andrew has just declared. The second part of that, though, is once a dose level is declared safe, we open that dose level for what we call pharmacodynamic expansion, and what that consists of, we recruit additional patients at a dose level, who, in addition to be meeting the standard eligibility for the program, now consent to have a fresh biopsy as well as a post-exposure biopsy. What that means is at day fifteen, so after two weeks of oral therapy, the patients come back in to a radiology suite and have a needle-guided core needle biopsy, and that provides us with tissue specimens, which allows us to interrogate what happened to the target after drug exposure. And so that gives us first read of connecting drug exposure pharmacokinetics with drug effect pharmacodynamics, including degradation of the target itself. Obviously, it is a phase I study, and efficacy is not the primary endpoint, but we will describe anti-tumor effects in all patients enrolled. The other thing that we've done in the study is we started to think about expanding dose levels that might be interesting and important. So you'll see in our previous disclosures that we alluded to or directed to adding melanoma patients at three hundred and twenty milligrams. And let me be clear that that wasn't because we're saying 320 mg is the RP2D. Okay. What we're saying is, 320 mg is a dose that's high enough to be interesting, and we think having more patients at that will help inform ultimate decision-making on the road to declaring an RP2D. And then the final piece that we've disclosed is that it's all well and good to interrogate monotherapy, but we also know that this drug may need EGFR blockade in colorectal cancer. Right. So we've opened cohorts to start to interrogate from a safety point of view, colorectal cancer. And on the horizon, we haven't opened it yet, we eventually will open cohorts to interrogate with a MEK inhibitor, with trametinib, which is of interest in melanoma and non-small cell lung cancer, as well as the other malignancies. So it's a really ambitious program, but- Yeah ... I hope you can see by all the different parts of that story, that we're creating data elements that help us, you know, get on the road to saying, obviously, is it safe, but do we have proof of mechanism? And do we have early proof of concept? And that data, in terms of the melanoma expansion and the combo, that won't be at ESMO. Right, yeah. Because those have just started fairly recently, and so there haven't been enough time to get that. So that, that'll be a future disclosure, but not next week. Got it. And just to go back to the patients enrolled. So can you like how heavily pre-treated are these patients? What have they already- Yeah. Kind of stepped through in terms of like, you know, different other treatments? Yeah. Yeah. The patients, the eligibility criteria are really pretty broad, but they basically states they must have had at least one prior regimen, but their regimen it should have included a BRAF inhibitor. Right. There's one asterisk on that, unless the patient comes from a region where that inhibitor is not available. But the bulk of the patients have had inhibitor-based therapy. Okay. That said, they've also had other therapy. Yeah. This is a phase I population being done. It's a phase I centers of excellence. So in fact, I think what you'll see is that, yes, they've had BRAF inhibitor therapy in the past, but they've also, in malignancy, like colorectal, have chemotherapy. In melanoma, they have had immunotherapy. Yeah. It represents patients who are not just been BRAF inhibitor exposed, but have really been exposed to the standard of care attempts to control the disease, per available treatment standards. I guess in terms of- The BRAF inhibitor therapy doesn't have to be their immediate prior therapy to come on the study. Okay. It just Okay. It just had to happen. They had to have had it- Yeah ... in their treatment journey. They may have had it one or two treatments ago. Some may have had it most recently. Yeah ... but it's not limiting that. Like, what would you expect at that advanced stage, like, in terms of like, you know, on therapy care, with like, type of response rates, like, you know, at that level of advanced disease? I think it's important to caveat in terms of what's an expected response rate in BRAF inhibitor-resistant patients who've also resistant to other standards of care. Yeah. I think the true answer to that is nobody knows. Yeah. Yeah. Maybe if I can take the liberty to reframe it a little bit. Sure. What would be an interesting response rate? Obviously, you know, the drug's not gonna work if it doesn't have anti-tumor responses. You know, I'd caveat my remarks by saying it's really important to note that based on the trial I just described. I t would be wildly inappropriate to expect to see enough patients with the same disease at the same dose level to start- Sure ... to calculate a response rate. But if at some point we need to get there, and I think when we get there, we'll be looking for response rates that we would argue are associated with meaningful clinical benefit. And so that number is a little bit of a moving target because, in fact, meaningful clinical benefit is a function of response rate times durability, sort of divided by safety. Yeah. And so if you simply talk about response rate without putting into, is it durable and is the drug safe? Yeah Y ou can end up with the wrong answer. Eventually, you know, we'll look to report that a predictable portion of patients are responding, that it's durable and safe, and obviously take that package to have engagement with regulatory agencies around it, you know, how to frame that for further development. But you know, I think the elephant in the room, if you will, for response rate, is that it's been reported in the literature that if patients had had previous BRAF inhibitor therapy and then have BRAF inhibitor therapy again, you might see a response rate of 20%. The caveat there is that those are, for the most part, uncontrolled studies, and durability is not reported. The other caveat, of course, is the fact that's actually, for the most part, in combination with a MEK inhibitor. So again, our initial data is monotherapy alone. So, you know, there's a lot to look for in our data set. But the response rate's not what you'll see. Right in the first part. And if you go back to the degrader rationale I articulated earlier, the idea- Yeah ... that we can overcome these resistance mechanisms- Yeah The benefit may not necessarily be in response rate. It may be in durability. Yeah. That's just gonna take a little bit longer. Yeah to prove out. And so that, that's, again, not... As Len said, it's a response rate, but durability is really important because, you know, a high response rate with a super short- Yeah Durable response, that doesn't help the patient. Yeah. I guess, how do you frame... So okay, obviously, you get past ESMO. We've got activity. Looks like you got a drug. In terms of like, you've already talked about some of the expansion cohorts, but how is kind of like the clinical development plan evolve, you know, from obviously, once you've gotten some activity and proof of mechanism here? Yeah. So I think, you know, the real important next steps as we talked about are enrolling the next cohort. So these melanoma monotherapy expansion cohort, the cetuximab combination, and eventually, the trametinib to understand what that can do to the response. 'Cause if you go back to some of our preclinical data, you know, the models are mixed. You know, we had some models where monotherapy, you know, and with a BRAF degrader plus trametinib didn't show any difference between the degrader alone, and some that it did, and so we want to understand that and how it works, you know, with a MEK or without, because we think physicians will want to understand that as well, so we need to get through that, and then we're really gonna be data-driven. You know, certainly the melanoma is an indication of interest as well as... I mean, all three, actually. Lung is the smallest. But I think we're gonna be data-driven, right? There are certainly, you know, after we get to full kind of proof of concept, you know, then we might move forward and, you know, for registrational studies in, you know, melanoma, CRC, but it's gonna be data-driven. So we're not ready to share what the specific plans are, but, you know, that would be how we think about developing it. Again, are these ones that you... In different tumor types, do you feel like you can take forward yourself, or is this stuff that you would look to go broader and maybe do a collaboration of some sort for, you know, some of these larger opportunities? Yeah, I mean, so this is also why we're accepting the program, is that we think it's a program that we can execute ourselves and we can really build the company around. You know, it's a big enough market that we can sustain, you know, a sort of initial commercial build-out. But at the same time, it's the treatment regimens are fairly standard and simple enough that we think it's easy. Drug development is not easy, but it is. We have the ability as a small company to execute in that kind of study. Yeah. I just contrast that to cemsidomide, right? Where it's a fairly complex, I would even call it treatment regimen or treatment paradigm, or a menu of treatments. And so development there becomes increasingly complex, and that's why we've... That's a program we probably need to find a partner. But for 1946, it's something we intend to take ourselves. Got it. And so, just want to be clear: So for this update, we're not gonna see any data for six forty, right? Or are we gonna- We've said at least four cohorts- Okay ... and thirty patients, so. You haven't specified which. We haven't specified specifically which. Okay. So. And then, are you going higher now that you've declared that safe, or are you gonna stop there? So we are allowed to go higher. I think we need to analyze some of the data to understand what exposures we're getting and, you know, make a determination about what we can. And I think it's... you know, Len and I both kind of have the philosophy that this is the time to explore the full range of what your drug can do, not later in development. That, that's... I've had experiences with that, and that can be very expensive. So, you know, I think our goal is to understand the full range of doses, and if the data suggests it's worth investigating a higher dose, then we will. Got it. Yeah, and in that regard, I think, you know, what we have to be prepared to do, it's a good problem to have. Based on the predicted safety profile, that this drug is gonna be very safe that we need to be prepared to make a dosing decision, which is not driven by exceeded the MTD. And so we're not going to just relentlessly push drug exposure in an attempt to find a mythical dose that exceeds the MTD. Yeah B ecause that really is not a good use of patient resources. At the same time, we don't want to prematurely stop dose escalation. So, you know, we've got enough dose steps now that we want to look at the data we have carefully in its totality and make a decision where we think the best value for the program is to be had. Again, coming back t o what I started by saying, is that we want to make sure that we, with the patients we have available, answer the questions that are important as quickly as possible. Really, there is synergy between what's important to investors, what's important to investigators and patients, and that is, do you have a drug that should stay in clinic and should continue to have investment placed in it and horsepower? Can you remind us preclinically, what level of degradation you needed to see to get that level of activity that you got excited about? I think, yeah. I mean, I think our preclinical data, and there's a big caveat, which I'll get to in a second. Our preclinical data, I think we demonstrated 80% degradation in the AACR presentation. But I will caution to say, I wouldn't jump to say that's the level of degradation you need in humans, for a couple of reasons. One, as most of you know, right, animal models are completely artificial systems. You're taking a hunk of human tumor and sticking it in the side of a mouse and trying to replicate, you know, sort of the real kind of in situ environment in a human, and so there's complications there. And then I think the methodologies are completely different. As Len mentioned, you know, if we're taking a core needle biopsy from not the primary tumor for resistance measurement, and then using IHC, which is a, you know, not exactly... It's a bit qualitative, as opposed to highly quantitative measure, measures of the protein, whereas preclinically, we can take the tumor out, grind it up, and actually measure protein levels. Yeah. I think there, you have to just take that with a grain of salt, and we're not being guided specifically by that, given just the difference in assay sort of fidelity. Yeah, and the other key difference is what Andrew just described to you in preclinical experiments is looking at responders versus non-responders, i.e., you know, the status. Yes. Yes. We're doing a completely unbiased look at the tissue. We don't know whether they're responders or non-responders when we take the tissue sample at fifteen days. That's the appropriate, unbiased way, and that's in fact what the agency wants you to do. Sure ... because you're trying to see, you know, what's happening in the microenvironment of the tumor after drug exposure. So there really is no appropriate straight line between the two, but suffice to say that we need to see degradation in the tissue, and that ultimately we need, we expect that degradation in the tissue will be associated with meaningful antitumor effects. Got it. Well, we're very excited to see the data, so that's exciting, and maybe we'll segue to cemsidomide and kind of get the program update there. I guess maybe just remind us kind of where you are, you know, with the program, and then obviously you're teeing up some data for later this year. Yeah. So I think our last update, we declared 75 safe, 75 micrograms, and we've expanded that into the expansion cohorts and we're enrolling there. We've done a really nice job of at the end of last year, right. We'd shared data from, you know, the 37.5, kind of on the 14-on 14-off schedule, daily dosing. We've escalated, you know, through kind of two escalations throughout the year. I think that you will have that data set in multiple myeloma, you know, for at least three dose levels. That's the data set you'll see. We're excited to share that, right? We saw very promising activity at the 37.5, and we've been able to escalate, you know, multiple times since then. I think, which is, you know, when we kind of dial all the way back to 2022, which I don't like to do, right? There were questions that, you know, does the drug even have a therapeutic index, right? Right. I think we've answered that. We've been able to- Yeah ... escalate, and we've declared multiple dose levels safe, and so we're excited to share, you know, a full data set, right, you know, as we shared in December of last year, on myeloma, and then I think NHL has been something no one's, not many people have focused on. You know, that data set is gonna be big, more complex to understand because it's in various subtypes of NHL, whereas the myeloma data is clearly in one indication, and so, you know, that will be more akin to the BRAF phase I data in the sense of it'll be different tumor types. We'll have to look at exposure, you know, PK/PD responses there as well. But you won't, you know, in terms of understanding, the specific activity in a specific subtype, that- Yeah ... that won't be able to do that in that data set. I guess, in terms of the update on the myeloma, how many patients would you expect there? I mean, obviously, you've been running that for longer, so like, it seems like you, you've got a little bit more of a critical mass of patients, but just I don't know if you can frame that for us. Yeah, I mean, but I think the key thing is it's still the same kind of paradigm where we do up to 10 patients- Yep ... per cohort. Got it. You know, if we get, you know, three doses at 10 patients, it's about 30 patients. Okay. So kind of similar. Gotcha. Okay, that's great. And I guess in terms of... So obviously, going back, you know, we saw those kind of high levels of neutropenia, and now that you've kind of figured out, you know, kind of the dosing interval, and you're starting to understand the doses and, you know, I guess how, what's an acceptable rate, I guess, of neutropenia, potentially, given that it's on target? And again, what- Yeah ... are physicians thinking? Like, is it even an issue for them really in practice? So, yeah. The neutropenia rate for a drug like cemsidomide, the rate is actually not important. It's the consequences of the rate. Okay, so you know, one of the things about trials in myeloma with IKZF1/3 degraders, it's kind of an artificial construct in that in cycle one, when it's a safety cohort, the patients are treated with the indicated dose, and they're followed for the first month. In our case, they get fourteen days of drug and fourteen days off. And we know that based on the class effect, that drug exposure is gonna be associated with a neutropenia-inducing event. The question is: How deep is the neutropenia-inducing event? Okay, so it's not that there's a way to give these drugs with zero neutropenia. That doesn't exist in this class of drugs. So that's the first thing. The second thing, the actual level of neutropenia itself is not particularly clinically relevant in real practice, because it's not a consequential thing in the absence of fever or infection. So in cycle one, you know, for the purposes of delineating sort of the classic pharmacokinetic/pharmacodynamic exposure curve, we do say that if a patient has a neutrophil count below five hundred for greater than seven days, that is considered a DLT. Or if they have an event, meaning irrespective of their neutrophil count, they have fever requiring antibiotics or a documented infection. That's for the purposes of declaring a dose level safe. And as Andrew just mentioned, what's worth emphasizing, we've now declared multiple dose levels safe with plus dex. So the idea that this drug has a narrow therapeutic index dispense with that. That's simply not true, okay, so that's great news- Yeah. for patients and everyone else. Now, the second part is what happens in real-life practice, and that's really what the expansion patients helped tell us. Mm-hmm. Because in the expansion, after the dose level is declared safe, we allow physicians to give G-CSF if they think they need it. Mm-hmm. So it's not prescribed as in, "You must give G-CSF," but in practice- Right -and this gets to the original premise of your question, what's an acceptable rate of neutropenia? Right. When physicians see a patient in their practice that looks like- Yeah their neutropenia is deep enough or prolonged enough to put them at risk, they give them Gs. Right. They can manage it. They can manage it. Yeah. And so we allow them to do that management in each one. So one of the things you'll see in the presentation as we update the data set is, you know, how does that all translate into a sort of practice pattern to make the case- Yep ... which we've made by inference, in terms of saying all these dose levels are declared safe, is that the drug has a wide therapeutic index. Got it. I guess, in terms of, like, timing for our PTD, like, is that something that's like, you know, a 2024 event, or do you think it's going to be a 2025 event in terms of the timing? You know, that's. I mean, that. So I think it's not a 2024 event, for sure. I think it. So the question is, you know, when is that? I would say, I think this drug is a drug that's likely to be active at multiple dose levels. And I think one of the things, when you look at the labels, right there's always, like, a typical dose reduction strategy. And I think that's important, and so, you know, we'll have to do the work. Mm-hmm ... going forward, you know, next to understand, you know, what's the optimal dose? Mm-hmm. And then, you know, what dose could you reduce to? But I think that's the benefit of the drug when I think about this compared to some of the others in the class, is we need to be active across multiple doses, and that's a real benefit because it lets physicians titrate as they need to. Whereas if you have a drug that works at only one dose or a very narrow range, it's challenging for physicians to use because you can't. You get no efficacy if you have to dial it back a little bit. Got it. And then, just in terms of the competitive landscape here, you know, obviously, you know, you got Bristol and, you know, other agents out there. I guess, how do you view your clinical development plan relative to theirs? And I guess, how do you kind of think about, you know, again, the overall landscape, you know, years from now? Yeah. It's, I mean, it's exciting for patients. There's been a lot of exciting new therapies that have come into the armamentarium recently in terms of the bispecifics, the CAR-Ts, and those are really benefiting patients. If I think about what BMS's registrational strategy is, it's pretty clear, and it makes sense for them. It appears to be replacing lenalidomide and pomalidomide with iberdomide and mezigdomide to protect the franchise going generic. Yeah. Right? That makes sense. But we don't have that franchise to protect, and so, you know, where we think the drug can be used is in combination with some of the newer agents. While they have really great response rates, patients do progress. You do see T- cell exhaustion with some of these newer treatments. And the data we presented last December, actually, in the monotherapy arm, you know, showed that we can activate T- cells, and so we think there's a nice combination strategy there. So for cemsidomide, we think that, you know, obviously you could develop it in the late line. Mm-hmm. You could develop it in the current standard regimens, but I think, you know, the smarter development strategy is to develop it in combination with the agents that are going to be established in the earlier lines of therapy, maybe aren't today. Mm-hmm. You know, a little bit of the Wayne Gretzky, "Go where the puck is going to be." And so that's how we think about it. You know, that said, you know, we think it's important, you know, as we said... as I said earlier, we need to find a partner for this program because it is fairly complex and expensive to develop it and maximize the value of the asset, you know, to patients and the owner of the asset. And so that's going to require a partner, and part of those details of that strategy will be driven by the partner. Got it. I guess, in terms of, like, when you think you're able to partner that asset, not in terms of timing, but in terms of, like, what level of data do you need? Yeah. Like, obviously, probably the data that we'll have by the end of the year, but, you know, going back to what you were saying in terms of, like, more work on dosing and trying to understand, like, how much of that do you think a partner really needs to see before, you know, dipping their toe in here? Yeah, I think our assumption, and I think, is that the data set that we'll share in Q4- Mm-hmm ... is going to be sufficient to find a partner. Got it. Okay. And then just more broadly, so, you know, in terms of just your degrader platform, so, I cover a bunch of the companies, you know, in the degrader area. I think early on, everyone was kind of talking about, "We have a differentiated platform. We can do this." Like, is that still true, or are we kind of just like... You know, where is the differentiation in the platforms? Yeah ... and where do you think, again, you might be differentiated relative to other platforms? Yeah. Look, I think there's some differentiation- Mm-hmm ... for sure. And I think our key things that we focus on in terms of designing degraders is, you know, the first thing is target selection. Sure. I think that is probably the most important thing that a degrader company can do, is to figure out, you know, what is the right target- Mm-hmm ... that leverages the benefits of a degrader. And again, that's why we really like the BRAF program, because- Sure ... the actual degrader mechanism solves some of the key liabilities of the inhibitor. And so, you know, one of the things that I always push the discovery team on is, like, why does the world need a degrader against this target? And there is a lot of different rationales that can be. It can be it's undruggable. Without a degrader, there's no other way to drug this target, and the biology is compelling. To, like, a BRAF, where, hey, there's a huge liability that inhibitors have or that existing treatments have, and degraders solve that. So that, that's the first thing. But then I think there's two things that I think differentiate us is, the first is our focus in optimizing degraders is on maximizing the catalytic activity of a degrader. For those of you that aren't familiar, one of the real benefits of a degrader is once it kind of introduces a target protein and an E3 ligase and makes that connection to tag it to be destroyed, it can actually go back and do it again. The speed with which that happens is really important because the deeper and faster you get rid of that protein, that's when you have the differential biology. Our focus is on optimizing for catalytic activity. Others may optimize for different steps in the process. Let's optimize the ternary complex, which is that complex of degrader, ligase, and target protein. That's an important step, but we've found in our process that optimizing that doesn't always lead to the best catalytic activity. Mm. And then the second key piece I'll point out is our focus on cereblon as our E3- Right ligase of choice. It sort of relates to the first point about catalytic activity. You know, we've probably made across all of our programs, both internal and partners, four hundred thousand different degraders as we try to optimize them. And one of the things that we've learned is really, really subtle changes in the exit vector of the cereblon binding or the ligase binding portion of the degrader has pretty big impact on the catalytic activity. And so because of that, we've invested in a library that's probably well over ten thousand compounds now of cereblon binders. That's all IP protected, that's a part of our cereblon toolkit, and that helps us optimize degraders. And so we haven't found a situation yet in terms of a target we're going after, where we need to do something different beyond cereblon. Yeah. That's not to say we wouldn't, but right now our focus has been on cereblon. Got it. And then maybe with the last couple of minutes, just in terms of being able to leverage that platform for some collaborations, so you already have some ongoing collaborations, so maybe you can give us update there and then just kind of your- Yeah Appetite for more. Yeah. So I would say, you know, we have a number of ongoing collaborations. Our oldest is the Roche collaboration. That was really a seminal collaboration that helped found the company back in twenty sixteen, and we've got two targets left on that program, but haven't been able to say much. But that's been a nice collaboration. And then Biogen, we announced earlier this year that we delivered a development candidate to them, which was exciting, and so we're looking forward to seeing how they progress, that we haven't yet shared, and aren't. They're gonna, you know, drive what gets shared about that program. And so that's been a great collaboration for us. And then we have two newer collaborations. In the end of last year, we announced a collaboration with Merck in the U.S. to use degraders as payloads in an antibody-drug conjugate, and this is something that's really exciting to us, and something when I joined the company, I thought would be a really good application, but it took us a while to find a company that had the right mindset to do it the way we thought it needed to be done. Whereas you all know ADCs, you can only hang a handful of molecules off of- Yeah the antibody, so you have to use highly toxic compounds. Inhibitors aren't potent enough to do that with. Degraders are because of this catalytic activity. So we can really expand sort of the intracellular targets that ADCs can go after by using a degrader as a payload. And so really excited about that sort of advance in terms of the application of degraders. And then the most recent one we announced was with Merck in Germany in KGaA. There were two targets in our pipeline that we felt needed a larger company to help really go after. And so we've got a collaboration there to develop two degraders against two critical oncogenic proteins, is all I can really say about that. But really excited about that opportunity because we think they're exciting targets. Got it. And then maybe just with the last minute, in terms of just, you know, beyond your current programs, what are you guys looking at? And like, you know, again, it looks like it sounds like for you guys, target selection is, you know, obviously the main core focus. So like, I guess, what's interesting to you right now in terms of the early-stage pipeline? Yeah, so we have not much to say- Yeah ... because we haven't, you know, for some competitive reasons, we're not really sharing yet- Mm - what we're working on, but certainly we have some exciting targets that are, you know, I'd say a mix of things that are sort of novel undruggables. Okay. but also things that are poorly drugged or- Right ... there's liabilities that we think that degraders can overcome. But beyond that, we haven't said much. Our focus is oncology. Yeah. That's where the team is. It's not to say in the future we wouldn't go beyond that. Some of our collaborations obviously are beyond that, and degraders have a broad application, not just in oncology, but that's just where our expertise is. And then actually, in terms of other collaborations, I think that, you know, it's got to be interesting scientifically. Mm-hmm. And it has to maybe help us pull the company to a different place or learn something from. We don't want to be a CRO, though. That's. So that's the key as we manage- Yeah ... those. You want to balance the internal versus collaborations. There's lots of benefits to collaboration. One of the things that we learned really from the Biogen collaboration is how to really understand CNS activity of degraders, and you see that in the BRAF program, where we were able to demonstrate CNS activity, you know, better than encorafenib. Yeah. They're not just sort of cash things. We should learn scientifically as we work with our partners. Got it. Cool. Well, I think we'll leave it there. Gentlemen, thank you so much for joining us. Great. Thanks. Good to see you. Thank you.